WO2006009092A1 - Method of effectively using medicine and method concerning prevention of side effect - Google Patents

Method of effectively using medicine and method concerning prevention of side effect Download PDF

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Publication number
WO2006009092A1
WO2006009092A1 PCT/JP2005/013113 JP2005013113W WO2006009092A1 WO 2006009092 A1 WO2006009092 A1 WO 2006009092A1 JP 2005013113 W JP2005013113 W JP 2005013113W WO 2006009092 A1 WO2006009092 A1 WO 2006009092A1
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WO
WIPO (PCT)
Prior art keywords
group
carbon atoms
amino
carbon
compound
Prior art date
Application number
PCT/JP2005/013113
Other languages
French (fr)
Japanese (ja)
Inventor
Shinji Kudou
Kazuhiko Kuriyama
Tokutarou Yasue
Original Assignee
Kyorin Pharmaceutical Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to BRPI0513110-3A priority Critical patent/BRPI0513110A/en
Priority to KR1020077003681A priority patent/KR101178318B1/en
Application filed by Kyorin Pharmaceutical Co., Ltd. filed Critical Kyorin Pharmaceutical Co., Ltd.
Priority to CA2573479A priority patent/CA2573479C/en
Priority to US11/631,128 priority patent/US7781617B2/en
Priority to AU2005264431A priority patent/AU2005264431B2/en
Priority to DE602005027074T priority patent/DE602005027074D1/en
Priority to AT05766305T priority patent/ATE502630T1/en
Priority to JP2006529167A priority patent/JP4917433B2/en
Priority to PL05766305T priority patent/PL1772145T3/en
Priority to EP05766305A priority patent/EP1772145B1/en
Priority to MX2007000564A priority patent/MX2007000564A/en
Priority to CN2005800238593A priority patent/CN101014329B/en
Priority to DK05766305.6T priority patent/DK1772145T3/en
Priority to SI200531284T priority patent/SI1772145T1/en
Publication of WO2006009092A1 publication Critical patent/WO2006009092A1/en
Priority to NO20070745A priority patent/NO338800B1/en
Priority to US12/650,899 priority patent/US7807854B2/en
Priority to AU2010241501A priority patent/AU2010241501B2/en

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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
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Definitions

  • the present invention has the effect of reducing lymphocytes circulating in the periphery and has a 2-amino-1,3-propandiol structure, a diallesulfide or dialyl ether compound, an immunosuppressant and Z
  • the present invention relates to a pharmaceutical comprising a combination with an anti-inflammatory agent, and relates to a method for effectively expressing an anti-inflammatory effect and reducing the occurrence of side effects.
  • a group of compounds having the first mechanism of action inhibits nucleoside synthesis in immune cells and stops the metabolism and immune activity of the cells.
  • This group includes azathioprine (Non-patent document 1), mizoribine (Non-patent document 2), mycophenolic acid (hereinafter sometimes abbreviated as "MPA", non-patent document 3), brequinar sodium (non-patent document Reference 4), leflunomide, and methotrexate.
  • MPA mycophenolic acid
  • brequinar sodium non-patent document Reference 4
  • leflunomide leflunomide
  • methotrexate methotrexate
  • the compound group having the second mechanism of action includes cyclosporin A (hereinafter sometimes abbreviated as "CsA”), tacrolimus (hereinafter sometimes abbreviated as "FK506”), and rapamycin (non- Patent document 5). These compounds interfere with the immune response by preventing the synthesis of effector cells by interfering with the synthesis of cytodynamic ins such as IL-2. Rapamycin, on the other hand, blocks the action of cytodynamic in-signal on immune cells.
  • CsA cyclosporin A
  • FK506 tacrolimus
  • rapamycin non- Patent document 5
  • Non-patent document 6 In order to reduce the side effects of individual immunosuppressive agents, other immunosuppressive agents such as CsA or FK506, or azathioprine and mizoribine (Non-patent document 6), (Non-patent document 7) may be used.
  • the treatment with steroids has been widely used, but at present, it does not necessarily exhibit a sufficient immunosuppressive effect without exhibiting toxic side effects.
  • Patent Document 1 As an aminopropanediol derivative having an immunosuppressive action, a combined effect of FTY720 and a calcium phosphate inhibitor is known (Patent Document 1). However, the development of new drugs is important in order to develop better effects and reduce side effects.
  • Non-Patent Document 1 Nature, 183: 1682 (1959).
  • Non-Patent Document 2 J. Clin. Invest., 87: 940 (1991).
  • Non-Patent Document 3 Pharm. Res., 7: 161 (1990).
  • Non-Patent Document 4 Transplantation, 53: 303 (1992).
  • Non-Patent Document 5 N. Eng. J. Med., 321: 1725 (1989); Transplant.Proc, 23: 2977 (1991)
  • Non-Patent Document 6 Transplant. Proc, 17: 1222 (1985).
  • Non-Patent Document 7 Clin. Transplant., 4: 191 (1990).
  • Patent Document 1 Japanese Patent Laid-Open No. 11-80026
  • the object of the present invention is to have low toxicity and can be used safely, and without causing side effects, it can be used in combination with conventional immunosuppressive compounds and anti-inflammatory drugs, and the immunosuppressive action and anti-inflammatory action are its effects. It is intended to provide a method for effectively maximizing the effects of the immunosuppressive agent and reducing the side effects of the anti-inflammatory agent.
  • the present inventors have an effect of reducing lymphocytes circulating in the periphery and have a 2-amino-1,3-propanediol structure, a diarylsulfide or diarylether compound, and other immunosuppression
  • the combined use with an anti-inflammatory agent or an anti-inflammatory agent can effectively cause the immunosuppressive or anti-inflammatory effect of the drug used in combination, and the side effects can be reduced by reducing the sufficient amount of the effect of other combined drugs. Finding what can be achieved and completing the present invention It is.
  • a diarylsulfide or diarylether compound having a 2-amino-1,3-propanediol structure that has the effect of reducing peripheral lymphocytes, an immunosuppressant, and Z or A medicine combined with an anti-inflammatory agent,
  • a diarylsulfide or diarylether compound having a 2-amino-1,3-propanediol structure which has the effect of reducing lymphocytes circulating in the periphery, has the general formula (1)
  • R is a halogen atom, a trihalomethyl group, a hydroxy group, a lower alkyl group having 1 to 7 carbon atoms, a phenyl group that may have a substituent, an aralkyl group, or a carbon number of 1 to 4 lower alkoxy group, trifluoromethyloxy group, phenoxy group, cyclohexylmethyloxy group, aralkyloxy group, pyridylmethyloxy group, cinnamyloxy group, naphthylmethyloxy group which may have a substituent Xyl group, phenoxymethyl group, hydroxymethyl group, hydroxyethyl group, lower alkylthio group having 1 to 4 carbon atoms, lower alkylsulfinyl group having 1 to 4 carbon atoms, lower alkylsulfol group having 1 to 4 carbon atoms, benzylthio group , Acetyl group, nitro group or cyano group, R is
  • the compound represented by the general formula (1) is 2-amino-2- [4 (3-benzyloxyphenol) -2-chlorosilane] ethyl-1,3-propanediol hydrochloride.
  • the medicine according to 2) is 2-amino-2- [4 (3-benzyloxyphenol) -2-chlorosilane] ethyl-1,3-propanediol hydrochloride.
  • the pharmaceutical agent according to 1) which is an immunosuppressant cattotrexate, or mycophenolic acid or mycophenolate mofetil.
  • Diarylsulfide or diarylether compounds having a 2-amino-1,3-propanediol structure which have the effect of reducing peripheral circulating lymphocytes, have excellent immunosuppressive effects even with a single agent. Power to exert The immunosuppressive effect of both drugs can be mutually enhanced by combined use with CsA and FK506, which are calci-eurin inhibitors. As a result, the amount of calci-eurin inhibitor used can be reduced, so that it is possible to avoid restrictions on clinical use of CsA and FK506 due to nephrotoxicity and hepatotoxicity, and to provide a highly safe and effective treatment.
  • MPA mycophenolate
  • the immunosuppressive effect of both drugs can be mutually enhanced.
  • MPA mycophenolate
  • methotrexate which is the first-line drug for the treatment of rheumatism, with the compound of the present application.
  • diarylsulfide or diarylether compounds with a 2-amino-1,3-propanediol structure that reduce peripheral lymphocytes are superior to adjuvant arthritis models even when used alone. Although it has an arthritis-inhibiting effect, it can be mutually enhanced by the combined use with methotxate, and the progression of arthritis can be suppressed with a combination of both drugs in a smaller amount.
  • Methotrexate is a drug with strong side effects, and the ability to perform small pulse therapy in the treatment of rheumatism According to the method of this application, the dose of methotrexate can be reduced, providing a treatment method that avoids side effects and is highly safe. it can.
  • FIG. 1 is a graph showing the single effect of KNF-299 in rat adjuvant arthritis.
  • ⁇ Normal control
  • ⁇ Adjuvant control
  • ⁇ KNF-299 O.lmg / kg.p. O.
  • FIG. 3 is a graph showing the combined effect of KNF-299 and MTX in rat adjuvant arthritis.
  • Adjuvant Contranore ⁇ : KNF-299 0.01mg / kg Mouth: MTX 0.025mg / kg: MTX 0.05mg / kg Black square: KNF—299 (0.01mgZkg) + MTX (0.025mg / kg)
  • KNF-299 O.Olmg / kg
  • MTX 0.05mg / kg
  • diarylsulfide or diarylether compound having an action of reducing lymphocytes circulating in the periphery of the present invention and having a 2-amino-1,3-propanediol structure is represented by the following general formula ( 1)
  • R represents a halogen atom, a trihalomethyl group, a hydroxy group, a lower alkyl group having 1 to 7 carbon atoms, a phenyl group which may have a substituent, an aralkyl group, or a carbon number of 1 to 4 lower alkoxy group, trifluoromethyloxy group, phenoxy group, cyclohexylmethyloxy group, aralkyloxy group, pyridylmethyloxy group, cinnamyloxy group, naphthylmethyloxy group which may have a substituent Xyl group, phenoxymethyl group, hydroxymethyl group, hydroxyethyl group, lower alkylthio group having 1 to 4 carbon atoms, lower alkylsulfinyl group having 1 to 4 carbon atoms, lower alkylsulfol group having 1 to 4 carbon atoms, benzylthio group , Acetyl group, nitro group or cyano group, R is hydrogen
  • Examples of the pharmacologically acceptable salt of the compound represented by the general formula (1) in the present invention include hydrochloride, hydrobromide, acetate, trifluoroacetate, methanesulfonate, and kenate. And acid addition salts such as tartrate.
  • the “halogen atom” represents a fluorine atom, a chlorine atom, a bromine atom or an iodine atom
  • the “trihalomethyl group” represents a trifluoromethyl group or a trichloromethyl group.
  • the “lower alkyl group having 1 to 7 carbon atoms” means, for example, straight chain or branched carbon atoms of 1 to 7 such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl, heptyl, etc. These hydrocarbons are mentioned.
  • the “optionally substituted phenoxy group” means a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, a trifluoromethyl group, a carbon number of 1 to 4 at an arbitrary position on the benzene ring. And those having a lower alkoxy group having 1 to 4 carbon atoms.
  • "Aralkyl”, “Aralkyl” Examples of the “aralkyl group” of the “oxy group” include a benzyl group, a diphenylmethyl group, a phenethyl group, and a phenylpropyl group.
  • a lower alkoxy group having 1 to 4 carbon atoms a lower alkylthio group having 1 to 4 carbon atoms”, “a lower alkyl sulfier group having 1 to 4 carbon atoms”, “a lower alkyl sulfo group having 1 to 4 carbon atoms”,
  • the “lower alkyl group” such as “a group” represents a linear or branched hydrocarbon having 1 to 4 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, etc., and may have a substituent.
  • Aralkyl group '' means a halogen atom such as fluorine atom, chlorine atom, bromine atom or iodine atom, trifluoromethyl group, lower alkyl group having 1 to 4 carbon atoms, or 1 to 4 carbon atoms at any position on the benzene ring. Examples thereof include those having a lower alkoxy group.
  • the compound of the present invention represented by the general formula (1) is disclosed in, for example, WO03 / 029184 and WO03 / 029205 and can be produced by the methods described in these publications.
  • the present invention is effective when used in combination with an immunosuppressant and Z or a drug having an anti-inflammatory action.
  • the immunosuppressive agent of the present invention does not include a diarylsulfide or diarylether compound having an action of reducing lymphocytes circulating in the periphery and having a 2-amino-1,3-propanediol structure. ! /.
  • Substances that can be used in combination include immunosuppressive and immunosuppressive agents that have an immunomodulatory action and Z or anti-immunity used for the treatment or prevention of acute or chronic rejection of allogeneic and xenografts, inflammatory diseases, and autoimmune diseases. It is an anti-inflammatory agent showing inflammation and malignant cell growth inhibition.
  • CsA and FK506 which are calci-eurin inhibitors, rapamycin, 40-0- (2-hydroxymethyl) -rapamycin, CCI779, ABT578, and ascomycins that have immunosuppressive effects ABT-281, ASM981 and mycophenolic acid (MPA), mycophenolate mofuethyl, azathioprine, mizoribine, cyclophosphamide and the like.
  • Antifolate antimetabolites such as methotrexate, widespread anti-adrenocortic steroids, immunomodulating auranofin, actalite, mesalazine or sulfasarazine, etc.
  • Anti-TNF-o; antibody infliximab, MRA is a 6-receptor antibody, and natalizumab is an anti-integrin antibody.
  • the dosage form of the compound can be changed depending on the properties of the compound, but can be prepared as an oral formulation or a parenteral formulation.
  • the active ingredients are mixed separately or simultaneously with physiologically acceptable carriers, excipients, binders, diluents, etc., and granules, powders, tablets, capsules, syrups, suppositories, suspensions, etc. It can be administered orally or parenterally as a suspension, solution, etc.
  • physiologically acceptable carriers excipients, binders, diluents, etc.
  • the active ingredients are formulated separately, they can be mixed and administered at the time of use, or can be administered simultaneously or continuously to the same patient with a time lag.
  • Formulations for such combinations are manufactured by conventional methods.
  • each active ingredient used in the combination can vary depending on the various active ingredients contained, the method of administration, or the condition of the subject to be treated.
  • ABT-281, ASM981 and mycophenolic acid (MPA) which are ascomycins with immunosuppressive action
  • MPA mycophenolic acid
  • 0.01 mg to 100 mg per day may be administered in one or several divided doses.
  • methotrexate which is an antifolate drug
  • 0.01 mg to 100 mg per day for an adult may be administered in one or several divided doses.
  • the immunosuppressant of the present application obtained in this way is an organ or tissue (for example, heart, kidney, liver, lung, bone marrow, cornea, spleen, small intestine, limb, muscle, nerve, fatty pulp, duodenum, Resistance to transplantation or transplant rejection (including xenotransplantation such as skin or splenocyte), bone marrow transplant-versus-host reaction (GVHD), rheumatoid arthritis, systemic lupus erythematosus, nephrotic syndrome, Hashimoto goiter, multiple sclerosis, myasthenia gravis, type I diabetes, type IV adult-onset diabetes, uveitis, steroid-dependent and steroid-resistant nephrosis, palmar plantar pustulosis, allergic cerebrospinal spinal cord It is useful for the prevention or treatment of autoimmune diseases such as inflammation and glomerulonephritis and inflammation caused by pathogenic microorganisms.
  • organ or tissue for example, heart,
  • psoriasis psoriasis, arthritic psoriasis, atopic eczema (atopic dermatitis), contact dermatitis and further eczema dermatitis, seborrheic dermatitis, lichen planus, pemphigus, bullous Pemphigus, Inflammation such as epidermolysis bullosa, hives, angioedema, cutaneous allergic vasculitis, erythema, cutaneous eosinophilia, acne, alopecia areata, eosinophilic fasciitis, and atherosclerosis It is useful for the prevention and treatment of proliferative and hyperproliferative skin diseases and immunogen-mediated diseases that appear in the skin.
  • the present invention is useful for the treatment of respiratory diseases such as sarcoidosis, pulmonary fibrosis, idiopathic interstitial pneumonia and reversible obstructive airway diseases represented by bronchial asthma, bronchitis and the like.
  • respiratory diseases such as sarcoidosis, pulmonary fibrosis, idiopathic interstitial pneumonia and reversible obstructive airway diseases represented by bronchial asthma, bronchitis and the like.
  • the present invention relates to conjunctivitis, keratoconjunctivitis, keratitis, spring catarrh, uveitis associated with Behcet's disease, herpetic keratitis, keratoconus, corneal epithelial dystrophy, corneal vitiligo, pemphigus vulgaris, Mohren ulcer, It may also be useful for the treatment of eye diseases such as membranitis, ocular muscle paralysis due to Graves' disease, and severe endophthalmitis.
  • the present invention also relates to inflammation of mucous membranes or blood vessels (for example, vascular injury caused by gastric ulcer, ischemic disease and thrombosis, ischemic bowel disease, inflammatory bowel disease (for example, Crohn's disease, ulcerative colitis). , Necrotizing enterocolitis) or intestinal disorders associated with burns are also useful.
  • mucous membranes or blood vessels for example, vascular injury caused by gastric ulcer, ischemic disease and thrombosis, ischemic bowel disease, inflammatory bowel disease (for example, Crohn's disease, ulcerative colitis).
  • Necrotizing enterocolitis or intestinal disorders associated with burns are also useful.
  • the present invention relates to renal diseases (for example, interstitial nephritis, Goodpastier I syndrome, hemolytic uremic syndrome and diabetic nephropathy), neurological diseases (polymyositis, Guillain-Barre syndrome, Meniere Disease and radiculopathy), endocrine disorders (such as hyperthyroidism and Graves' disease), blood disorders (aplastic anemia, hypoplastic anemia, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia) , Granulocytopenia, lack of erythropoiesis), bone disease (such as osteoporosis), respiratory disease (such as sarcoidosis, pulmonary fibrosis, idiopathic interstitial pneumonia), skin disease (dermatomyositis, vitiligo vulgaris, vulgaris) Ichthyosis, photoallergic hypersensitivity, cutaneous T-cell lymphoma, etc.), cardiovascular diseases (arteriosclerosis, aortitis,
  • the present invention also provides enterocolitis or allergic diseases (celiac disease, proctitis, eosinophilic gastroenteritis, erythroderma, Crohn's disease, ulcerative colitis), and symptomatics away from the gastrointestinal tract. It is also useful for the treatment of food-related allergies that show symptoms (eg migraine, rhinitis, eczema) possible.
  • the present invention has a liver regeneration action and an action of promoting Z or hepatocyte hypertrophy and hyperplasia. Therefore, immunogenic diseases (e.g. autoimmune hepatitis, primary biliary cirrhosis, chronic autoimmune liver diseases such as sclerosing cholangitis), partial hepatectomy, acute liver necrosis (e.g. toxins) , Viral hepatitis, necrosis due to shock or oxygen deficiency), hepatitis B, hepatitis C, and liver diseases such as cirrhosis are useful for prevention and treatment.
  • immunogenic diseases e.g. autoimmune hepatitis, primary biliary cirrhosis, chronic autoimmune liver diseases such as sclerosing cholangitis), partial hepatectomy, acute liver necrosis (e.g. toxins) , Viral hepatitis, necrosis due to shock or oxygen deficiency), hepatitis B, hepatitis C, and
  • the present invention relates to malignant rheumatoid arthritis, amyloidosis, fulminant hepatitis, Shy-Drager syndrome, pustular psoriasis, Behcet's disease, systemic lupus erythematosus, endocrine ocular palsy, progressive systemic sclerosis, Mixed connective tissue disease, aortitis syndrome, ugener granulomatosis, active chronic hepatitis, evans syndrome, hay fever, idiopathic hypoparathyroidism, addison's disease (autoimmune adrenitis), autoimmune testicularitis, Autoimmune ovitis, cold hemagglutinin, paroxysmal cold hemagglutinin, pernicious anemia, adult T-cell leukemia, autoimmune atrophic gastritis, lupus leprosy, tubular interstitial nephritis, membra
  • KNF-299 2 amino-2- [4- (3-benzyloxyphenylthio) 2 chlorophenol-ethyl] 1,3 propanediol
  • cyclosporine 2 amino-2- [4- (3-benzyloxyphenylthio) 2 chlorophenol-ethyl] 1,3 propanediol
  • CsA tacrolimus
  • FK506 tacrolimus
  • methotrexer HMTX methotrexer HMTX
  • mycophenolic acid MPA
  • a full-thickness skin graft (1.8 ⁇ 1.8 cm) prepared by donor abdomen was placed. Attached so that the center pad of the emergency bandage (30X72 mm) is on the graft, and further ventilated tape (adhesive bandage, 3.8 X 15
  • the drug is administered once a day, daily, 0.5 mL / 100 g.
  • B.W. was administered orally. Distilled water was administered to the control group.
  • CsA was administered by diluting Sandimiyun injection solution (50 mg / mL) with distilled water.
  • FK506 suspends the contents of Prograf Capsules (Fujisawa Pharmaceutical) with distilled water.
  • KNF-299 was administered after being dissolved in distilled water.
  • the administration solutions were mixed and administered immediately before administration.
  • Graft rejection was determined by observing the graft every day from day 5 after transplantation with the bandage removed, and determining that more than 90% of the graft epithelium was necrotic and browned as rejection. . The number of days until the rejection of transplantation was confirmed was taken as the survival period.
  • the median value is the third longest engraftment period.
  • KNF-299 has the effect of extending the average survival time by 27 days or more when administered alone at 3 mg / kg.
  • CsA and FK506 are administered alone, prolonged survival is observed at 30 mg / kg and 10 mg / kg for 30 days or longer, respectively.
  • Table 1 shows the results of testing the combined effect at a dose lower than the dose at which the engraftment prolonging effect was observed when administered alone.
  • KNF-299 was clearly shown to prolong graft survival when administered alone at 3 mg / kg. Also, CsA
  • CsA 10 mg / kg, KNF-299 0.0 3 mg / kg is a dose that allows only 1 to 4 days longer than the control, but when both are used in combination, 30 days or longer An extension was observed in all cases, and an excellent rejection-inhibiting effect could be induced. This is also the case with FK506, with a single dose administered at a low dose. In the combination group of FK506 3 mg / kg and KNF-299 0.1 mg / kg, the mean survival time was 26 days or more, and a clear combination effect was observed.
  • KNF-299 can enhance the effects of calciurin inhibitors such as CsA and FK506.
  • the ability to reduce the amount of Kalsh-Eurin inhibitor used increases the possibility of avoiding restrictions on clinical use due to the development of nephrotoxicity and hepatotoxicity, and provides an effective treatment.
  • MTX showed inhibition rates of 20% and 35% when 0.025 mg / kg and 0.05 mg / kg alone were administered.
  • MTX is a folic acid anti-metabolite and is known to cause bone marrow suppression, interstitial pneumonia, etc. as side effects. It became clear that KNF-299 has an excellent combination effect on the AA model when used in combination with MTX, which is the most effective first-line drug in clinical practice. Therefore, it seems to be effective by using KNF-299 in combination with refractory rheumatism patients who are less effective for MTX. MTX is a drug with strong side effects, and a small amount of pulse therapy is used for the treatment of rheumatism. Even in this case, side effects may occur, and side effects can be reduced by using folic acid together. By using KNF-299 in combination with MTX, the dose of MTX or KNF-299 can be reduced, side effects can be avoided, and a highly safe treatment can be provided.
  • the drug was administered by oral administration once a day, every day, on the day of heart transplantation.
  • MPA is 0.5% of Wako Junyaku purchased
  • Carboxymethylcellulose, 0.4% Tween80, and 0.9% benzyl alcohol-containing physiological saline was prepared to 20 mg / mL and administered at O.lmL / lOOgB.W.
  • KNF-299 dissolves in distilled water at 0.06mg / mL, 0.5mL / 100g
  • the control group received the solvent used in the MPA administration solution.
  • the heartbeat of the transplanted heart was confirmed by visual inspection or palpation, and it was judged as rejection when the heartbeat stopped.
  • the number of days until the rejection of transplantation was confirmed was taken as the engraftment period.
  • the average value of the survival period of each group was calculated as the average number of survival days (MST). For combinations between strains that strongly cause rejection
  • Table 2 shows the results of studying the rejection suppression effect of the transplanted heart.
  • diarylsulfide or diaryletherification which has the effect of reducing lymphocytes circulating in the periphery and has a 2-amino-1,3-propanediol structure Combined with a combination of immunosuppressive and anti-inflammatory agents such as C, which is an excellent immunosuppressive effect even with a single agent, CsA and FK506, which are calcineurin inhibitors, and myco-funolic acid (MPA), which is a nucleoside synthesis inhibitor To enhance the effect.
  • immunosuppressive and anti-inflammatory agents such as C, which is an excellent immunosuppressive effect even with a single agent, CsA and FK506, which are calcineurin inhibitors, and myco-funolic acid (MPA), which is a nucleoside synthesis inhibitor
  • the clinical doses of CsA, FK506, and mofethyl mycophenolate can be reduced, so that the use of calciurin drugs due to nephrotoxicity or hepatotoxicity or nucleoside synthesis neutropenia can be avoided, which is safe.
  • a highly effective treatment can be provided.
  • the dose of methotrexate can be reduced, and side effects can be avoided and a highly safe treatment can be provided. In other words, a sufficient anti-inflammatory effect can be achieved even with a small amount of the combined drug, and it can be used safely for a long period of time, effectively and continuously suppressing the progression and recurrence of rheumatic conditions. I can expect.
  • the present invention has the effect of reducing lymphocytes circulating in the periphery of a 2-amino-1,3-propanediol structure, a diarylsulfide or a diarylether compound, an immunosuppressive agent, and a Z or antiinflammatory agent.
  • a pharmaceutical comprising a combination of and is useful as a means for effectively expressing an immunosuppressive action and an anti-inflammatory action and reducing the occurrence of side effects.
  • Such drugs are used to prevent or treat inflammation caused by autoimmune diseases and pathogenic microorganisms, foreign antigens, exogenous substances, and prevent inflammatory, proliferative and hyperproliferative skin diseases and immunogen-mediated diseases that appear in the skin. Useful for treatment.

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Abstract

A medicine which effectively functions as an immunosuppressant or anti-inflammatory agent and is effective in diminishing the occurrence of side effects. The medicine comprises a combination of: a diaryl sulfide or diaryl ether compound having a 2-amino-1,3-propanediol structure and having the function of diminishing lymphocytes circulating through the periphery; and an immunosuppressant and/or an anti-inflammatory agent.

Description

明 細 書  Specification
効果的な医薬の使用法及び副作用発現の防御に関する方法  Method for effective use of medicine and method for prevention of side effect
技術分野  Technical field
[0001] 本発明は末梢を循環するリンパ球を減少させる作用を有し 2—アミノー 1, 3—プロ パンジオール構造を有するジァリールスルフイド又はジァリールエーテル化合物と免 疫抑制剤及び Z又は抗炎症剤とを組み合せてなる医薬に関し、かつ免疫抑制作用 ゃ抗炎症作用を効果的に発現させ且つ副作用発現を減少させる方法に関するもの である。  [0001] The present invention has the effect of reducing lymphocytes circulating in the periphery and has a 2-amino-1,3-propandiol structure, a diallesulfide or dialyl ether compound, an immunosuppressant and Z Alternatively, the present invention relates to a pharmaceutical comprising a combination with an anti-inflammatory agent, and relates to a method for effectively expressing an anti-inflammatory effect and reducing the occurrence of side effects.
背景技術  Background art
[0002] 免疫応答を抑制する方法の開発は、臓器および細胞移植における拒絶反応を防 ぎ、種々の自己免疫疾患を治療および予防する上できわめて重要である。従来より 免疫応答の抑制に使用されてきたィ匕合物は、（1)特定の免疫細胞を攻撃してかかる 細胞を免疫系から除去する力 あるいは (2)免疫細胞がサイト力インに応答する能力 を阻害することによって、免疫応答に関わる細胞数を減少させるという作用機作を有 するものである。応答する細胞数が少なくなると、免疫系は通常と同様の応答反応を 起こすことができなくなり、その結果免疫応答抑制が起こる。  [0002] The development of a method for suppressing an immune response is extremely important in preventing rejection in organs and cell transplants, and in treating and preventing various autoimmune diseases. Traditionally, compounds that have been used to suppress immune responses are either (1) the ability to attack specific immune cells to remove such cells from the immune system or (2) immune cells respond to site force in It has a mechanism of action that decreases the number of cells involved in the immune response by inhibiting the ability. When the number of responding cells decreases, the immune system cannot respond as usual, resulting in suppression of the immune response.
[0003] 具体的には、第一の作用機作を有する化合物群は、免疫細胞中でのヌクレオシド 合成を阻害して当該細胞の代謝および免疫活性を停止させる。この群には、ァザチ ォプリン (非特許文献 1)、ミゾリビン (非特許文献 2)、ミコフエノール酸 (以下、「MPA」 と略する場合がある、非特許文献 3)、ブレキナールナトリウム (非特許文献 4)、レフル ノミド、メトトレキサートが挙げられる。し力しながら、これらの化合物には毒性の副作 用を生じ易いという問題点がある。  [0003] Specifically, a group of compounds having the first mechanism of action inhibits nucleoside synthesis in immune cells and stops the metabolism and immune activity of the cells. This group includes azathioprine (Non-patent document 1), mizoribine (Non-patent document 2), mycophenolic acid (hereinafter sometimes abbreviated as "MPA", non-patent document 3), brequinar sodium (non-patent document Reference 4), leflunomide, and methotrexate. However, these compounds have the problem that they are prone to toxic side effects.
[0004] 第二の作用機作を有する化合物群には、シクロスポリン A (以下、「CsA」と略称する 場合がある）、タクロリムス（以下、「FK506」と略称する場合がある）およびラパマイシン (非特許文献 5)等がある。これらの化合物は、 IL-2などのサイト力インの合成を妨げ ることによりエフェクター細胞の増殖'分化が誘導されず免疫反応を妨げる。一方、ラ パマイシンはサイト力インシグナルが免疫細胞に作用するのをブロックする。 [0005] 個々の免疫抑制剤の副作用を軽減するために、 CsAまたは FK506 、ずれかとァザ チォプリンゃミゾリビン (非特許文献 6)、（非特許文献 7)のような他の免疫抑制剤もし くはステロイド類を併用した治療が広く用いられてきたが、必ずしも毒性の副作用を 示すことなく十分な免疫抑制効果を発揮するには至っていないのが現状である。 [0004] The compound group having the second mechanism of action includes cyclosporin A (hereinafter sometimes abbreviated as "CsA"), tacrolimus (hereinafter sometimes abbreviated as "FK506"), and rapamycin (non- Patent document 5). These compounds interfere with the immune response by preventing the synthesis of effector cells by interfering with the synthesis of cytodynamic ins such as IL-2. Rapamycin, on the other hand, blocks the action of cytodynamic in-signal on immune cells. [0005] In order to reduce the side effects of individual immunosuppressive agents, other immunosuppressive agents such as CsA or FK506, or azathioprine and mizoribine (Non-patent document 6), (Non-patent document 7) may be used. The treatment with steroids has been widely used, but at present, it does not necessarily exhibit a sufficient immunosuppressive effect without exhibiting toxic side effects.
[0006] 免疫抑制作用を有するァミノプロパンジオール誘導体としては FTY720とカルシ-ュ 一リン阻害剤との併用効果が公知となっている（特許文献 1)。し力しながら、より優れ た作用の発現や副作用の低減のために、新たな薬剤の開発は重要である。  [0006] As an aminopropanediol derivative having an immunosuppressive action, a combined effect of FTY720 and a calcium phosphate inhibitor is known (Patent Document 1). However, the development of new drugs is important in order to develop better effects and reduce side effects.
非特許文献 1 : Nature, 183: 1682(1959).  Non-Patent Document 1: Nature, 183: 1682 (1959).
非特許文献 2 : J. Clin. Invest., 87:940(1991).  Non-Patent Document 2: J. Clin. Invest., 87: 940 (1991).
非特許文献 3 : Pharm. Res., 7: 161(1990).  Non-Patent Document 3: Pharm. Res., 7: 161 (1990).
非特許文献 4: Transplantation, 53: 303(1992).  Non-Patent Document 4: Transplantation, 53: 303 (1992).
非特許文献 5 :N. Eng. J. Med., 321:1725 (1989); Transplant. Proc, 23: 2977 (1991) 非特許文献 6 : Transplant. Proc, 17:1222 (1985).  Non-Patent Document 5: N. Eng. J. Med., 321: 1725 (1989); Transplant.Proc, 23: 2977 (1991) Non-Patent Document 6: Transplant. Proc, 17: 1222 (1985).
非特許文献 7 : Clin. Transplant., 4:191 (1990).  Non-Patent Document 7: Clin. Transplant., 4: 191 (1990).
特許文献 1：特開平 11-80026号公報  Patent Document 1: Japanese Patent Laid-Open No. 11-80026
発明の開示  Disclosure of the invention
発明が解決しょうとする課題  Problems to be solved by the invention
[0007] 本発明の目的は、それ自体毒性が低く安全に使用できるとともに、副作用を生じるこ となく従来の免疫抑制化合物ゃ抗炎症薬と併用し、その効果である免疫抑制作用や 抗炎症作用を効果的に最大限に引き出すと共に免疫抑制剤ゃ抗炎症剤の副作用 を減少させる方法を提供するものである。 [0007] The object of the present invention is to have low toxicity and can be used safely, and without causing side effects, it can be used in combination with conventional immunosuppressive compounds and anti-inflammatory drugs, and the immunosuppressive action and anti-inflammatory action are its effects. It is intended to provide a method for effectively maximizing the effects of the immunosuppressive agent and reducing the side effects of the anti-inflammatory agent.
課題を解決するための手段  Means for solving the problem
[0008] 本発明者らは、末梢を循環するリンパ球を減少させる作用を有し 2—アミノー 1, 3 - プロパンジオール構造を有するジァリールスルフイド又はジァリールエーテル化合物 と他の免疫抑制剤あるいは抗炎症剤との併用により併用した薬剤の免疫抑制作用あ るいは抗炎症作用を効果的に発現させることができ、さらに併用他剤の効果発現十 分量を減少させることで副作用の低減が図れることを見出し、本発明を完成したもの である。 [0008] The present inventors have an effect of reducing lymphocytes circulating in the periphery and have a 2-amino-1,3-propanediol structure, a diarylsulfide or diarylether compound, and other immunosuppression The combined use with an anti-inflammatory agent or an anti-inflammatory agent can effectively cause the immunosuppressive or anti-inflammatory effect of the drug used in combination, and the side effects can be reduced by reducing the sufficient amount of the effect of other combined drugs. Finding what can be achieved and completing the present invention It is.
[0009] 即ち、本発明は  [0009] That is, the present invention provides
1) 末梢を循環するリンパ球を減少させる作用を有し 2—アミノー 1, 3—プロパンジ オール構造を有するジァリールスルフイド又はジァリールエーテルィ匕合物と、免疫抑 制剤及び Z又は抗炎症剤とを組み合わせてなる医薬、  1) A diarylsulfide or diarylether compound having a 2-amino-1,3-propanediol structure that has the effect of reducing peripheral lymphocytes, an immunosuppressant, and Z or A medicine combined with an anti-inflammatory agent,
2) 末梢を循環するリンパ球を減少させる作用を有し 2—アミノー 1, 3—プロパンジ オール構造を有するジァリールスルフイド又はジァリールエーテルィ匕合物が一般式（ 1)  2) A diarylsulfide or diarylether compound having a 2-amino-1,3-propanediol structure, which has the effect of reducing lymphocytes circulating in the periphery, has the general formula (1)
[0010] [化 1]
Figure imgf000004_0001
[0010] [Chemical 1]
Figure imgf000004_0001
[0011] [式中、 Rはハロゲン原子、トリハロメチル基、ヒドロキシ基、炭素数 1〜7の低級アル キル基、置換基を有しても良いフエ二ル基、ァラルキル基、炭素数 1〜4の低級アル コキシ基、トリフルォロメチルォキシ基、フエノキシ基、シクロへキシルメチルォキシ基 、置換基を有しても良いァラルキルォキシ基、ピリジルメチルォキシ基、シンナミルォ キシ基、ナフチルメチルォキシ基、フエノキシメチル基、ヒドロキシメチル基、ヒドロキシ ェチル基、炭素数 1〜4の低級アルキルチオ基、炭素数 1〜4の低級アルキルスルフ ィニル基、炭素数 1〜4の低級アルキルスルホ-ル基、ベンジルチオ基、ァセチル基 、ニトロ基又はシァノ基を示し、 Rは水素原子、ハロゲン原子、トリノ、ロメチル基、炭素 [In the formula, R is a halogen atom, a trihalomethyl group, a hydroxy group, a lower alkyl group having 1 to 7 carbon atoms, a phenyl group that may have a substituent, an aralkyl group, or a carbon number of 1 to 4 lower alkoxy group, trifluoromethyloxy group, phenoxy group, cyclohexylmethyloxy group, aralkyloxy group, pyridylmethyloxy group, cinnamyloxy group, naphthylmethyloxy group which may have a substituent Xyl group, phenoxymethyl group, hydroxymethyl group, hydroxyethyl group, lower alkylthio group having 1 to 4 carbon atoms, lower alkylsulfinyl group having 1 to 4 carbon atoms, lower alkylsulfol group having 1 to 4 carbon atoms, benzylthio group , Acetyl group, nitro group or cyano group, R is hydrogen atom, halogen atom, trino, romethyl group, carbon
2  2
数 1〜4の低級アルコキシ基、炭素数 1〜7の低級アルキル基、フ ネチル基又はべ ンジルォキシ基を示し、 Rは水素原子、ハロゲン原子、トリフルォロメチル基、炭素数  Represents a lower alkoxy group having 1 to 4 carbon atoms, a lower alkyl group having 1 to 7 carbon atoms, a phenethyl group or a benzyloxy group, and R represents a hydrogen atom, a halogen atom, a trifluoromethyl group, or a carbon number.
3  Three
1〜4の低級アルコキシ基、ヒドロキシ基、ベンジルォキシ基、炭素数 1〜7の低級ァ ルキル基、フエ-ル基、炭素数 1〜4の低級アルコキシメチル基又は炭素数 1〜4の 低級アルキルチオ基を示し、 Xは 0、 S、 SO又は SOを示し、 nは 1〜4の整数を示す  1 to 4 lower alkoxy group, hydroxy group, benzyloxy group, 1 to 7 carbon lower alkyl group, phenol group, 1 to 4 carbon lower alkoxymethyl group or 1 to 4 carbon lower alkylthio group X represents 0, S, SO or SO, n represents an integer of 1 to 4
2  2
]  ]
で表される化合物又は薬学的に許容される塩ならびに水和物である 1)記載の医薬、 3) 前記一般式（1)で表される化合物が 2—アミノー 2— [4一（3—べンジルォキシ フエ-ルチオ）ー2—クロ口フエ-ル]ェチルー 1, 3—プロパンジオールである 2)に記 載の医薬、 Or a pharmaceutically acceptable salt and hydrate of 1), 3) the compound represented by the general formula (1) is 2-amino-2- [4 (3- Benzyloxy (Phenolthio) -2-chloro-diethyl] ethyl-1,3-propanediol, 2)
4) 前記一般式（1)で表される化合物が 2—アミノー 2— [4一（3—べンジルォキシ フエ-ルチオ）ー2—クロ口フエ-ル]ェチルー 1, 3—プロパンジオール塩酸塩である 2)に記載の医薬、  4) The compound represented by the general formula (1) is 2-amino-2- [4 (3-benzyloxyphenol) -2-chlorosilane] ethyl-1,3-propanediol hydrochloride. The medicine according to 2),
5) 免疫抑制剤がカルシニューリン阻害薬である 1)に記載の医薬、  5) The medicament according to 1), wherein the immunosuppressive agent is a calcineurin inhibitor,
6) カルシュ-ユーリン阻害剤がシクロスポリン A又はタクロリムスである 5)に記載の 免疫抑制剤、  6) The immunosuppressive agent according to 5), wherein the Carche-Eurin inhibitor is cyclosporin A or tacrolimus,
7)免疫抑制剤カ^トトレキサート又はミコフエノール酸若しくはミコフエノール酸モフ ェチルである 1)に記載の医薬、  7) The pharmaceutical agent according to 1), which is an immunosuppressant cattotrexate, or mycophenolic acid or mycophenolate mofetil.
8)末梢を循環するリンパ球を減少させる作用を有する 2—ァミノ—1, 3—プロパン ジオール構造を有するジァリールスルフイド又はジァリールエーテルィ匕合物と、免疫 抑制剤及び Z又は抗炎症剤とを組み合せてなる医薬により、相互の薬効を増強し、 また、使用量を減少させることで副作用発現の防御に関する方法、  8) 2-amino-1,3-propanediol having a function of reducing lymphocytes circulating in the periphery, diallesulfide or dialyl ether compound having a diol structure, an immunosuppressant and Z or By using a medicine combined with an inflammatory agent, the mutual efficacy is enhanced, and a method for preventing the occurrence of side effects by reducing the amount used,
に関するものである。 It is about.
発明の効果 The invention's effect
末梢を循環するリンパ球を減少させる作用を有する 2—アミノー 1, 3—プロパンジォ ール構造を有するジァリールスルフイド又はジァリールエーテル化合物は単剤によつ ても優れた免疫抑制効果を発揮する力 カルシ-ユーリン阻害剤である CsAや FK506 との併用により、両薬物の免疫抑制効果を相互に増強することができる。その結果、 カルシ-ユーリン阻害剤の使用量を減量できるため、臨床おける CsAや FK506の腎 毒性や肝毒性による使用制限を回避でき、安全性の高い効果的な治療法を提供で きる。また、ヌクレオシド合成を阻害して免疫細胞の代謝および免疫活性を停止させ る作用を持つミコフヱノール酸 (MPA)との併用にお ヽても両薬剤の免疫抑制効果を 相互に増強することができ、 MPAの使用量を減量することで下痢、嘔気などの消ィ匕器 症状、汎血球減少や好中球減少、二次的感染症、リンパ腫の発現を回避することが でき、安全性が高く十分な治療を提供できる。さらに、リウマチ治療における第一選 択薬であるメトトレキサートと本出願化合物との併用においても同様である。すなわち 、末梢を循環するリンパ球を減少させる作用を有し 2—アミノー 1, 3—プロパンジォー ル構造を有するジァリールスルフイド又はジァリールエーテル化合物はアジュバント 関節炎モデルにぉ ヽて単剤でも優れた関節炎発症抑制効果を示すが、メトトキサー トとの併用により、その効果を相互に増強し合い、より少量の両薬物の組み合せで関 節炎の進行を抑制することが可能である。メトトレキサートは副作用の強い薬剤であり 、リウマチ治療では少量パルス療法を行っている力 本出願の方法によればメトトキ サ―トの投与量を減量でき、副作用の回避と安全性の高い治療法を提供できる。つ まり、メトトレキサートの少量でも効果が発現することで、安全に長期間使用することが 可能になりリウマチの病態の進行や再発を効果的に且つ持続的に抑制することが期 待できる。 Diarylsulfide or diarylether compounds having a 2-amino-1,3-propanediol structure, which have the effect of reducing peripheral circulating lymphocytes, have excellent immunosuppressive effects even with a single agent. Power to exert The immunosuppressive effect of both drugs can be mutually enhanced by combined use with CsA and FK506, which are calci-eurin inhibitors. As a result, the amount of calci-eurin inhibitor used can be reduced, so that it is possible to avoid restrictions on clinical use of CsA and FK506 due to nephrotoxicity and hepatotoxicity, and to provide a highly safe and effective treatment. Moreover, even when used in combination with mycophenolate (MPA), which inhibits nucleoside synthesis and stops immune cell metabolism and immune activity, the immunosuppressive effect of both drugs can be mutually enhanced. By reducing the amount of MPA used, it is possible to avoid diarrhea, nausea and other extinguisher symptoms, pancytopenia and neutropenia, secondary infections, and lymphomas. Can provide the right treatment. The same applies to the combined use of methotrexate, which is the first-line drug for the treatment of rheumatism, with the compound of the present application. Ie Furthermore, diarylsulfide or diarylether compounds with a 2-amino-1,3-propanediol structure that reduce peripheral lymphocytes are superior to adjuvant arthritis models even when used alone. Although it has an arthritis-inhibiting effect, it can be mutually enhanced by the combined use with methotxate, and the progression of arthritis can be suppressed with a combination of both drugs in a smaller amount. Methotrexate is a drug with strong side effects, and the ability to perform small pulse therapy in the treatment of rheumatism According to the method of this application, the dose of methotrexate can be reduced, providing a treatment method that avoids side effects and is highly safe. it can. In other words, an effect is manifested even with a small amount of methotrexate, so that it can be used safely for a long period of time, and the progression and recurrence of rheumatic conditions can be expected to be effectively and continuously suppressed.
図面の簡単な説明  Brief Description of Drawings
[0013] [図 1]ラットアジュバント関節炎における KNF-299の単独効果を示すグラフ。 ♦:ノー マル コントロール ◊:アジュバント コントロール 黒四角： KNF— 299 0.03mg/k g.p. o. □: KNF -299 O.lmg/kg.p. o.  FIG. 1 is a graph showing the single effect of KNF-299 in rat adjuvant arthritis. ♦: Normal control ◊: Adjuvant control Black square: KNF— 299 0.03mg / k g.p. o. □: KNF-299 O.lmg / kg.p. O.
[図 2]ラットアジュバント関節炎におけるメトトレキサート (MTX)の単独効果を示すダラ フ。 參：アジュバント コントロール 口：ノーマル コントロール Δ : ΜΤΧ 0.03mg
Figure imgf000006_0001
[Figure 2] Daraf showing the single effect of methotrexate (MTX) in rat adjuvant arthritis.參: Adjuvant control Mouth: Normal control Δ: ΜΤΧ 0.03mg
Figure imgf000006_0001
[図 3]ラットアジュバント関節炎における KNF-299と MTXの併用効果を示すグラフ。 〇：アジュバント コントローノレ Δ : KNF-299 0.01mg/kg 口： MTX 0.025mg /kg : MTX 0.05mg/kg 黒四角： KNF— 299 (0.01mgZkg) +MTX(0.025 mg/kg) ♦： KNF - 299 (O.Olmg/kg) +MTX(0.05mg/kg)  FIG. 3 is a graph showing the combined effect of KNF-299 and MTX in rat adjuvant arthritis. ○: Adjuvant Contranore Δ: KNF-299 0.01mg / kg Mouth: MTX 0.025mg / kg: MTX 0.05mg / kg Black square: KNF—299 (0.01mgZkg) + MTX (0.025mg / kg) ♦: KNF-299 (O.Olmg / kg) + MTX (0.05mg / kg)
発明を実施するための最良の形態  BEST MODE FOR CARRYING OUT THE INVENTION
[0014] 本発明の末梢を循環するリンパ球を減少させる作用を有し 2—アミノー 1, 3—プロ パンジオール構造を有するジァリールスルフイド又はジァリールエーテル化合物とし ては下記一般式（1) [0014] The diarylsulfide or diarylether compound having an action of reducing lymphocytes circulating in the periphery of the present invention and having a 2-amino-1,3-propanediol structure is represented by the following general formula ( 1)
[0015] [化 2]
Figure imgf000007_0001
[0015] [Chemical 2]
Figure imgf000007_0001
[0016] [式中、 Rはハロゲン原子、トリハロメチル基、ヒドロキシ基、炭素数 1〜7の低級アル キル基、置換基を有しても良いフエ二ル基、ァラルキル基、炭素数 1〜4の低級アル コキシ基、トリフルォロメチルォキシ基、フエノキシ基、シクロへキシルメチルォキシ基 、置換基を有しても良いァラルキルォキシ基、ピリジルメチルォキシ基、シンナミルォ キシ基、ナフチルメチルォキシ基、フエノキシメチル基、ヒドロキシメチル基、ヒドロキシ ェチル基、炭素数 1〜4の低級アルキルチオ基、炭素数 1〜4の低級アルキルスルフ ィニル基、炭素数 1〜4の低級アルキルスルホ-ル基、ベンジルチオ基、ァセチル基 、ニトロ基又はシァノ基を示し、 Rは水素原子、ハロゲン原子、トリノ、ロメチル基、炭素 [Wherein, R represents a halogen atom, a trihalomethyl group, a hydroxy group, a lower alkyl group having 1 to 7 carbon atoms, a phenyl group which may have a substituent, an aralkyl group, or a carbon number of 1 to 4 lower alkoxy group, trifluoromethyloxy group, phenoxy group, cyclohexylmethyloxy group, aralkyloxy group, pyridylmethyloxy group, cinnamyloxy group, naphthylmethyloxy group which may have a substituent Xyl group, phenoxymethyl group, hydroxymethyl group, hydroxyethyl group, lower alkylthio group having 1 to 4 carbon atoms, lower alkylsulfinyl group having 1 to 4 carbon atoms, lower alkylsulfol group having 1 to 4 carbon atoms, benzylthio group , Acetyl group, nitro group or cyano group, R is hydrogen atom, halogen atom, trino, romethyl group, carbon
2  2
数 1〜4の低級アルコキシ基、炭素数 1〜7の低級アルキル基、フ ネチル基又はべ ンジルォキシ基を示し、 Rは水素原子、ハロゲン原子、トリフルォロメチル基、炭素数  Represents a lower alkoxy group having 1 to 4 carbon atoms, a lower alkyl group having 1 to 7 carbon atoms, a phenethyl group or a benzyloxy group, and R represents a hydrogen atom, a halogen atom, a trifluoromethyl group, or a carbon number.
3  Three
1〜4の低級アルコキシ基、ヒドロキシ基、ベンジルォキシ基、炭素数 1〜7の低級ァ ルキル基、フエ-ル基、炭素数 1〜4の低級アルコキシメチル基又は炭素数 1〜4の 低級アルキルチオ基を示し、 Xは 0、 S、 SO又は SOを示し、 nは 1〜4の整数を示す  1 to 4 lower alkoxy group, hydroxy group, benzyloxy group, 1 to 7 carbon lower alkyl group, phenol group, 1 to 4 carbon lower alkoxymethyl group or 1 to 4 carbon lower alkylthio group X represents 0, S, SO or SO, n represents an integer of 1 to 4
2  2
]で表される化合物又は薬学的に許容される塩ならびに水和物である。  Or a pharmaceutically acceptable salt and hydrate thereof.
本発明における一般式（1)で表される化合物の薬理学的に許容される塩には、塩 酸塩、臭化水素酸塩、酢酸塩、トリフルォロ酢酸塩、メタンスルホン酸塩、クェン酸塩 、酒石酸塩のような酸付加塩が挙げられる。  Examples of the pharmacologically acceptable salt of the compound represented by the general formula (1) in the present invention include hydrochloride, hydrobromide, acetate, trifluoroacetate, methanesulfonate, and kenate. And acid addition salts such as tartrate.
[0017] 本発明の一般式（1)において、「ハロゲン原子」とはフッ素原子、塩素原子、臭素原 子、ヨウ素原子を表し、「トリハロメチル基」とはトリフルォロメチル基、トリクロロメチル基 を表し、「炭素数 1〜7の低級アルキル基」とは、例えばメチル、ェチル、プロピル、ィ ソプロピル、ブチル、 tーブチル、ペンチル、へキシル、ヘプチルなどの直鎖もしくは 分岐した炭素数 1〜7の炭化水素が挙げられる。「置換基を有しても良いフエノキシ基 」とは、ベンゼン環上の任意の位置にフッ素原子、塩素原子、臭素原子、ヨウ素原子 などのハロゲン原子、トリフルォロメチル基、炭素数 1〜4の低級アルキル基、炭素数 1〜4の低級アルコキシ基を有するものが挙げられる。「ァラルキル基」、「ァラルキル ォキシ基」の「ァラルキル基」とはべンジル基、ジフエ-ルメチル基、フエネチル基、フ ェニルプロピル基が挙げられる。また「炭素数 1〜4の低級アルコキシ基」、「炭素数 1 〜4の低級アルキルチオ基」、「炭素数 1〜4の低級アルキルスルフィエル基」、「炭素 数 1〜4の低級アルキルスルホ-ル基」などの「低級アルキル基」とは、例えばメチル、 ェチル、プロピル、イソプロピル、ブチルなどの直鎖もしくは分岐した炭素数 1〜4の 炭化水素を表し、「置換基を有しても良いァラルキル基」とは、ベンゼン環上の任意の 位置にフッ素原子、塩素原子、臭素原子、ヨウ素原子などのハロゲン原子、トリフルォ ロメチル基、炭素数 1〜4の低級アルキル基、炭素数 1〜4の低級アルコキシ基を有 するものが挙げられる。 In the general formula (1) of the present invention, the “halogen atom” represents a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, and the “trihalomethyl group” represents a trifluoromethyl group or a trichloromethyl group. The “lower alkyl group having 1 to 7 carbon atoms” means, for example, straight chain or branched carbon atoms of 1 to 7 such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl, heptyl, etc. These hydrocarbons are mentioned. The “optionally substituted phenoxy group” means a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, a trifluoromethyl group, a carbon number of 1 to 4 at an arbitrary position on the benzene ring. And those having a lower alkoxy group having 1 to 4 carbon atoms. "Aralkyl", "Aralkyl" Examples of the “aralkyl group” of the “oxy group” include a benzyl group, a diphenylmethyl group, a phenethyl group, and a phenylpropyl group. In addition, “a lower alkoxy group having 1 to 4 carbon atoms”, “a lower alkylthio group having 1 to 4 carbon atoms”, “a lower alkyl sulfier group having 1 to 4 carbon atoms”, “a lower alkyl sulfo group having 1 to 4 carbon atoms”, The “lower alkyl group” such as “a group” represents a linear or branched hydrocarbon having 1 to 4 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, etc., and may have a substituent. `` Aralkyl group '' means a halogen atom such as fluorine atom, chlorine atom, bromine atom or iodine atom, trifluoromethyl group, lower alkyl group having 1 to 4 carbon atoms, or 1 to 4 carbon atoms at any position on the benzene ring. Examples thereof include those having a lower alkoxy group.
[0018] より具体的には 2 アミノー 2— [4— (3 ベンジルォキシフエ-ルチオ） 2 クロ口 フエ-ル]ェチルー 1, 3 プロパンジオールまたはその塩酸塩が挙げられる。  [0018] More specifically, 2-amino-2- [4- (3 benzyloxyphenylthio) 2 chlorophenol] ethyl-1,3 propanediol or its hydrochloride may be mentioned.
[0019] 一般式（1)で示される本発明化合物は、例えば WO03/029184及び WO03/029205 などで開示されており、これらの公報の方法によって製造することができる。  The compound of the present invention represented by the general formula (1) is disclosed in, for example, WO03 / 029184 and WO03 / 029205 and can be produced by the methods described in these publications.
[0020] 本発明は、免疫抑制剤及び Z又は抗炎症作用を持つ薬剤との併用において、効 果を発揮する。なお、本発明の免疫抑制剤には、末梢を循環するリンパ球を減少さ せる作用を有し 2 アミノー 1, 3 プロパンジオール構造を有するジァリールスルフィ ド又はジァリールエーテル化合物は含まれな！/、。  [0020] The present invention is effective when used in combination with an immunosuppressant and Z or a drug having an anti-inflammatory action. Note that the immunosuppressive agent of the present invention does not include a diarylsulfide or diarylether compound having an action of reducing lymphocytes circulating in the periphery and having a 2-amino-1,3-propanediol structure. ! /.
[0021] 併用でき得る物質としては、同種および異種移植の急性あるいは慢性拒絶、炎症 性疾患、自己免疫疾患の治療や予防に用いる免疫抑制、免疫調節作用を有する免 疫抑制剤及び Z又は、抗炎症、悪性細胞増殖抑制を示す抗炎症剤である。  [0021] Substances that can be used in combination include immunosuppressive and immunosuppressive agents that have an immunomodulatory action and Z or anti-immunity used for the treatment or prevention of acute or chronic rejection of allogeneic and xenografts, inflammatory diseases, and autoimmune diseases. It is an anti-inflammatory agent showing inflammation and malignant cell growth inhibition.
[0022] 具体的にはカルシ-ユーリン阻害薬である CsAや FK506、 mTOR阻害薬であるラパ マイシン、 40- 0- (2-ヒドロキシメチル)ーラパマイシン、 CCI779、 ABT578、免疫抑制作 用を持つァスコマイシン類である ABT- 281、 ASM981及びミコフエノール酸 (MPA)、ミコ フエノール酸モフエチル、ァザチォプリン，ミゾリビン、シクロフォスフアミドなどがある。 また葉酸代謝拮抗薬であるメトトレキサート、広く抗炎症作用を示す副腎皮質ステロイ ド、免疫調節作用のあるオーラノフィン、ァクタリット、メサラジンまたはスルフアサラジ ンなどゃ抗 TNF- o;抗体であるインフリキシマブ、抗 IL-6受容体抗体である MRA、抗 インテグリン抗体であるナタリズマブなどがある。 [0023] 併用する際は個別にあるいは同時に患者へ投与できる。また、混合物、単独での 投与が可能である。化合物の剤形は、化合物の性状に応じて変更可能であるが、経 口製剤または非経口製剤として調製可能である。すなわち有効成分を、別々にある いは同時に、生理学的に許容されうる担体、賦形剤、結合剤、希釈剤などと混合し、 顆粒剤、粉剤、錠剤、カプセル剤、シロップ剤、座薬、懸濁剤、溶液剤などとして、経 口的に又は非経口的に投与することができる。有効成分を別々に製剤化した場合に は、それぞれを使用時に混合して投与するか、又は同時に、あるいは時間差をおい て継続的に同一の患者に投与することもできる。このような組み合わせのための製剤 は、通常の方法によって製造する。 [0022] Specifically, CsA and FK506, which are calci-eurin inhibitors, rapamycin, 40-0- (2-hydroxymethyl) -rapamycin, CCI779, ABT578, and ascomycins that have immunosuppressive effects ABT-281, ASM981 and mycophenolic acid (MPA), mycophenolate mofuethyl, azathioprine, mizoribine, cyclophosphamide and the like. Antifolate antimetabolites such as methotrexate, widespread anti-adrenocortic steroids, immunomodulating auranofin, actalite, mesalazine or sulfasarazine, etc.Anti-TNF-o; antibody infliximab, MRA is a 6-receptor antibody, and natalizumab is an anti-integrin antibody. [0023] When used in combination, it can be administered individually or simultaneously to the patient. In addition, the mixture can be administered alone. The dosage form of the compound can be changed depending on the properties of the compound, but can be prepared as an oral formulation or a parenteral formulation. That is, the active ingredients are mixed separately or simultaneously with physiologically acceptable carriers, excipients, binders, diluents, etc., and granules, powders, tablets, capsules, syrups, suppositories, suspensions, etc. It can be administered orally or parenterally as a suspension, solution, etc. When the active ingredients are formulated separately, they can be mixed and administered at the time of use, or can be administered simultaneously or continuously to the same patient with a time lag. Formulations for such combinations are manufactured by conventional methods.
[0024] 組み合わせに使用するそれぞれの有効成分の投与量は、含有する種々の有効成 分、投与方法あるいは治療対象の状態によって変化し得る。通常、一般式（1)の化 合物と例えば、カルシ-ユーリン阻害薬である CaAや FK506、 mTOR阻害薬であるラ ノ マイシン、 40- 0- (2-ヒドロキシメチル)ーラパマイシン、 CCI779、 ABT578、免疫抑制 作用を持つァスコマイシン類である ABT- 281、 ASM981及びミコフエノール酸 (MPA)な どと組み合せて用いる場合は、成人 1日あたり 0.01mg〜100mgを 1回又は数回に分け て投与すればよい。また、葉酸代謝拮抗薬であるメトトレキサートと組み合せて用いる 場合においても、成人 1日あたり 0.01mg〜100mgを 1回又は数回に分けて投与すれば よい。  [0024] The dose of each active ingredient used in the combination can vary depending on the various active ingredients contained, the method of administration, or the condition of the subject to be treated. Usually, the compound of the general formula (1) and, for example, CaA and FK506, which are calci-eurin inhibitors, romycin, which is an mTOR inhibitor, 40-0- (2-hydroxymethyl) -rapamycin, CCI779, ABT578, When used in combination with ABT-281, ASM981 and mycophenolic acid (MPA), which are ascomycins with immunosuppressive action, 0.01 mg to 100 mg per day may be administered in one or several divided doses. Good. In addition, when used in combination with methotrexate, which is an antifolate drug, 0.01 mg to 100 mg per day for an adult may be administered in one or several divided doses.
[0025] このようにして得られる本出願の免疫抑制剤は器官または組織 (例えば、心臓、腎 臓、肝臓、肺、骨髄、角膜、脾臓、小腸、肢、筋肉、神経、脂肪髄、十二指腸、皮膚ま たは脾島細胞等、異種移植を含む)の移植に対する抵抗性または移植拒絶反応、骨 髄移植による移植片対宿主反応症 (GVHD)、リウマチ性関節炎、全身性エリテマトー デス、ネフローゼ症候群、橋本甲状腺腫、多発性硬化症、重症筋無力症、 I型糖尿 病、 Π型成人発症型糖尿病、ブドウ膜炎、ステロイド依存性およびステロイド抵抗性ネ フローゼ、手掌足底膿疱症、アレルギー性脳脊髄炎、糸球体腎炎等のような自己免 疫疾患および病原微生物による炎症の予防または治療に有用である。  [0025] The immunosuppressant of the present application obtained in this way is an organ or tissue (for example, heart, kidney, liver, lung, bone marrow, cornea, spleen, small intestine, limb, muscle, nerve, fatty pulp, duodenum, Resistance to transplantation or transplant rejection (including xenotransplantation such as skin or splenocyte), bone marrow transplant-versus-host reaction (GVHD), rheumatoid arthritis, systemic lupus erythematosus, nephrotic syndrome, Hashimoto goiter, multiple sclerosis, myasthenia gravis, type I diabetes, type IV adult-onset diabetes, uveitis, steroid-dependent and steroid-resistant nephrosis, palmar plantar pustulosis, allergic cerebrospinal spinal cord It is useful for the prevention or treatment of autoimmune diseases such as inflammation and glomerulonephritis and inflammation caused by pathogenic microorganisms.
[0026] また、乾癬、関節症性乾癬、アトピー性湿疹 (アトピー性皮膚炎)、接触性皮膚炎お よびさらなる湿疹性皮膚炎、脂漏性皮膚炎、扁平苔癬、天疱瘡、水疱性類天疱瘡、 表皮水疱症、蓴麻疹、血管浮腫、皮膚アレルギー性血管炎、紅斑、皮膚好酸球増加 症、ざ瘡、円形脱毛症、好酸球性筋膜炎、並びに粥状硬化症のような炎症性、増殖 性および高増殖性の皮膚病および皮膚に現れる免疫原媒介性疾患の予防および 治療に有用である。 [0026] Also, psoriasis, arthritic psoriasis, atopic eczema (atopic dermatitis), contact dermatitis and further eczema dermatitis, seborrheic dermatitis, lichen planus, pemphigus, bullous Pemphigus, Inflammation such as epidermolysis bullosa, hives, angioedema, cutaneous allergic vasculitis, erythema, cutaneous eosinophilia, acne, alopecia areata, eosinophilic fasciitis, and atherosclerosis It is useful for the prevention and treatment of proliferative and hyperproliferative skin diseases and immunogen-mediated diseases that appear in the skin.
[0027] さらに本発明は、呼吸疾患、例えば、サルコイド症、肺線維症、特発性間質性肺炎 および気管支喘息に代表される可逆性閉塞性気道疾患、気管支炎等の治療に有用 である。  Furthermore, the present invention is useful for the treatment of respiratory diseases such as sarcoidosis, pulmonary fibrosis, idiopathic interstitial pneumonia and reversible obstructive airway diseases represented by bronchial asthma, bronchitis and the like.
さらに、本発明は、結膜炎、角結膜炎、角膜炎、春季カタル、ベーチェット病に伴う ブドウ膜炎、ヘルぺス性角膜炎、円錐角膜、角膜上皮ジストロフィー、角膜白斑、眼 天疱瘡、モーレン潰瘍、強膜炎、バセドウ病による眼筋麻痺、重篤な眼内炎などの眼 病の治療にも有用であり得る。  Furthermore, the present invention relates to conjunctivitis, keratoconjunctivitis, keratitis, spring catarrh, uveitis associated with Behcet's disease, herpetic keratitis, keratoconus, corneal epithelial dystrophy, corneal vitiligo, pemphigus vulgaris, Mohren ulcer, It may also be useful for the treatment of eye diseases such as membranitis, ocular muscle paralysis due to Graves' disease, and severe endophthalmitis.
[0028] また、本発明は、粘膜または血管の炎症 (例えば、胃潰瘍、虚血性疾患および血栓 症に起因する血管損傷、虚血性腸疾患、炎症性腸疾患 (例えばクローン病、潰瘍性 大腸炎)、壊死性腸炎)または熱傷に伴う腸障害の予防および治療にも有用である。  [0028] The present invention also relates to inflammation of mucous membranes or blood vessels (for example, vascular injury caused by gastric ulcer, ischemic disease and thrombosis, ischemic bowel disease, inflammatory bowel disease (for example, Crohn's disease, ulcerative colitis). , Necrotizing enterocolitis) or intestinal disorders associated with burns are also useful.
[0029] さらに、本発明は、腎疾患 (例えば間質性腎炎、グッドパスチヤ一症候群、溶血性 ***症候群および糖尿病性腎症など）、神経疾患 (多発性筋炎、ギラン ·バレー症 候群、メニエール病および神経根症など）、内分泌性疾患（甲状腺機能亢進症およ びバセドウ病など）、血液疾患 (再生不良性貧血、低形成貧血、特発性血小板減少 性紫斑病、自己免疫性溶血性貧血、顆粒球減少症、赤血球形成欠如など）、骨疾患 (骨粗鬆症など)、呼吸疾患 (サルコイド症、肺線維症、特発性間質性肺炎など)、皮 膚病 (皮膚筋炎、尋常性白斑、尋常性魚鱗癬、光アレルギー性過敏症、皮膚 T細胞 リンパ腫など)、循環器疾患 (動脈硬化症、大動脈炎、結節性多発動脈炎、心筋炎な ど）、コラーゲン病（強皮症、ゥェゲナー肉芽腫症、シエーダレン症候群など）、アジポ 一シス、好酸球性筋膜炎、歯周病、ネフローゼ症候群、溶血性***症候群および 筋ジストロフィーの予防および治療にも有用である。  [0029] Further, the present invention relates to renal diseases (for example, interstitial nephritis, Goodpastier I syndrome, hemolytic uremic syndrome and diabetic nephropathy), neurological diseases (polymyositis, Guillain-Barre syndrome, Meniere Disease and radiculopathy), endocrine disorders (such as hyperthyroidism and Graves' disease), blood disorders (aplastic anemia, hypoplastic anemia, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia) , Granulocytopenia, lack of erythropoiesis), bone disease (such as osteoporosis), respiratory disease (such as sarcoidosis, pulmonary fibrosis, idiopathic interstitial pneumonia), skin disease (dermatomyositis, vitiligo vulgaris, vulgaris) Ichthyosis, photoallergic hypersensitivity, cutaneous T-cell lymphoma, etc.), cardiovascular diseases (arteriosclerosis, aortitis, polyarteritis nodosa, myocarditis, etc.), collagen disease (scleroderma, Wegener granulomas) Disease, Siedalen syndrome Etc.), Ajipo one cis, eosinophilic fasciitis, gum disease, nephrotic syndrome, is also useful in the prevention and treatment of hemolytic uremic syndrome and muscular dystrophy.
[0030] また、本発明は、腸炎またはアレルギー症 (セリアック病、直腸炎、好酸球性胃腸炎 、紅皮症、クローン病、潰瘍性大腸炎）、並びに胃腸管から離れたところで症候性の 病徴 (例えば、偏頭痛、鼻炎、湿疹）を示す食物関連アレルギー症の治療にも有用で あり得る。 [0030] The present invention also provides enterocolitis or allergic diseases (celiac disease, proctitis, eosinophilic gastroenteritis, erythroderma, Crohn's disease, ulcerative colitis), and symptomatics away from the gastrointestinal tract. It is also useful for the treatment of food-related allergies that show symptoms (eg migraine, rhinitis, eczema) possible.
[0031] 本発明は、肝臓再生作用および Zまたは肝細胞の肥大および過形成を促進する 作用を有する。それ故、免疫原性の疾患 (例えば自己免疫肝炎、原発性胆汁性肝硬 変、硬化性胆管炎のような慢性自己免疫肝臓病など)、部分的な肝臓切除、急性肝 臓壊死 (例えば毒素、ウィルス肝炎、ショックまたは酸欠に起因する壊死）、 B型肝炎 、 C型肝炎、並びに肝硬変などの肝臓病の予防および治療に有用である。  [0031] The present invention has a liver regeneration action and an action of promoting Z or hepatocyte hypertrophy and hyperplasia. Therefore, immunogenic diseases (e.g. autoimmune hepatitis, primary biliary cirrhosis, chronic autoimmune liver diseases such as sclerosing cholangitis), partial hepatectomy, acute liver necrosis (e.g. toxins) , Viral hepatitis, necrosis due to shock or oxygen deficiency), hepatitis B, hepatitis C, and liver diseases such as cirrhosis are useful for prevention and treatment.
[0032] さらに、本発明は悪性関節リウマチ、アミロイド症、劇症肝炎、シャイ'ドレーガー症 候群、膿疱性乾癬、ベーチェット病、全身性エリテマトーデス、内分泌性眼筋麻痺、 進行性全身性硬化症、混合結合組織病、大動脈炎症候群、ゥ ゲナー肉芽腫症、 活動性慢性肝炎、ェヴアンス症候群、花粉症、特発性上皮小体機能低下症、アジソ ン病（自己免疫副腎炎）、自己免疫***、自己免疫卵巣炎、寒冷赤血球凝集素、 発作性寒冷赤血球凝集素、悪性貧血、成人 T細胞白血病、自己免疫萎縮性胃炎、 類狼瘡肝炎、尿細管間質性腎炎、膜性腎症、筋萎縮性側索硬化症、リウマチ熱、心 筋梗塞後症候群および交感性眼炎の予防および治療にも有用であり得る。  [0032] Further, the present invention relates to malignant rheumatoid arthritis, amyloidosis, fulminant hepatitis, Shy-Drager syndrome, pustular psoriasis, Behcet's disease, systemic lupus erythematosus, endocrine ocular palsy, progressive systemic sclerosis, Mixed connective tissue disease, aortitis syndrome, ugener granulomatosis, active chronic hepatitis, evans syndrome, hay fever, idiopathic hypoparathyroidism, addison's disease (autoimmune adrenitis), autoimmune testicularitis, Autoimmune ovitis, cold hemagglutinin, paroxysmal cold hemagglutinin, pernicious anemia, adult T-cell leukemia, autoimmune atrophic gastritis, lupus leprosy, tubular interstitial nephritis, membranous nephropathy, muscle atrophy It may also be useful in the prevention and treatment of lateral sclerosis, rheumatic fever, post-myocardial infarction syndrome and sympathetic ophthalmitis.
[0033] 実施例  [0033] Examples
以下に実施例を挙げて本発明を具体的に説明する。本実施例では特に一般式の 化合物のうち、 2 アミノー 2— [4— (3—ベンジルォキシフエ-ルチオ） 2 クロロフ ェ -ル]ェチルー 1, 3 プロパンジオール（以下、「KNF-299」と略記する）およびシク ロスポリン  The present invention will be specifically described below with reference to examples. In this example, among the compounds of the general formula, 2 amino-2- [4- (3-benzyloxyphenylthio) 2 chlorophenol-ethyl] 1,3 propanediol (hereinafter referred to as “KNF-299”) (Abbreviated) and cyclosporine
A (CsA)、タクロリムス（FK506)、メトトレキサー HMTX)及びミコフエノール酸 (MPA)と を組み合わせについて述べる力 本発明はこれらの実施例によって何ら限定される ものではない。  The ability to describe combinations of A (CsA), tacrolimus (FK506), methotrexer HMTX) and mycophenolic acid (MPA) The present invention is not limited in any way by these examples.
実施例 1  Example 1
[0034] 耍 織；商合遣伝早^!合体 商合ラット 統間の同 皮膚移植片の 羞延  [0034] Weaving; Commerce and intercommunication transmission!
MHCを一致させたラット同種異系皮膚移植を、文献 (A.m. J. Rat allogeneic skin grafts matched with MHC are described in the literature (A.m.
Med. TechnoL; 36, 149-157, 1970、 Transplant. Proc; 28, 1056-1059, 1996)等を参 考にして、下記の方法で行った。 1群 5匹で検討し、すべてのラットは個別ケージで飼 育した。ドナーとして LEWCRTl1)、レシピエントとして F344 (RT1M)を選択した。レシピ ェントの背部に移植床を作製し、ペニシリン溶液 (4万 U/mL、 in Med. TechnoL; 36, 149-157, 1970, Transplant. Proc; 28, 1056-1059, 1996). Consider 5 animals per group and all rats are kept in individual cages. I grew up. LEWCRTl 1 ) was selected as the donor and F344 (RT1 M ) was selected as the recipient. Prepare a transplant bed on the back of the recipe and use penicillin solution (40,000 U / mL, in
生理食塩水)を数滴たらした後、ドナー腹部カゝら調製した全層植皮片（1.8X1.8 cm) を置いた。救急絆創膏 (30X72 mm)の中央パットが移植片の上になるように貼り付け 、さらに通気テープ (粘着包帯、 3.8 X 15  After dropping several drops of physiological saline, a full-thickness skin graft (1.8 × 1.8 cm) prepared by donor abdomen was placed. Attached so that the center pad of the emergency bandage (30X72 mm) is on the graft, and further ventilated tape (adhesive bandage, 3.8 X 15
cm)で巻き付けた。 5日目に絆創膏と通気テープをハサミで切開して取り除いた。  cm). On the fifth day, the bandage and the ventilation tape were cut off with scissors and removed.
[0035] 薬物の投与は、皮膚移植当日から、 1日 1回、毎日、 0.5mL/100g [0035] From the day of skin transplantation, the drug is administered once a day, daily, 0.5 mL / 100 g.
B.W.を経口投与した。コントロール群には蒸留水を投与した。 CsAはサンディミユン注 射液 (50mg/mL)を蒸留水で希釈して投与した。 FK506はプログラフカプセル (藤沢薬 品)の内容物を蒸留水で懸濁し  B.W. was administered orally. Distilled water was administered to the control group. CsA was administered by diluting Sandimiyun injection solution (50 mg / mL) with distilled water. FK506 suspends the contents of Prograf Capsules (Fujisawa Pharmaceutical) with distilled water.
て投与した。 KNF-299は蒸留水に溶解して投与した。また、併用投与群には、投与 直前に各投与液を混合して投与した。  Administered. KNF-299 was administered after being dissolved in distilled water. In the combination administration group, the administration solutions were mixed and administered immediately before administration.
[0036] 移植片拒絶の判定は、絆創膏を取り外した移植後 5日目からは毎日、移植片を観 察し、移植片上皮の 90%以上が壊死して褐色になった状態を拒絶と判定した。移植 力も拒絶が確認されるまでの日数を生着期間とした。 [0036] Graft rejection was determined by observing the graft every day from day 5 after transplantation with the bandage removed, and determining that more than 90% of the graft epithelium was necrotic and browned as rejection. . The number of days until the rejection of transplantation was confirmed was taken as the survival period.
[0037] 各群の生着期間の平均値を平均生着日数 (MST)として算出した。また、各群 (n=5[0037] The average value of the survival period of each group was calculated as the average survival period (MST). Each group (n = 5
)において 3番目に長い生着期間を中央値とした。 The median value is the third longest engraftment period.
[0038] KNF-299はその 3mg/kgの単独投与にお!、て平均生着日数を 27日以上延長する 効果を有する。また、 CsA、 FK506の単独投与ではそれぞれ 30mg/kg、 10mg/kgで 30 日以上の生着延長が観察される。 [0038] KNF-299 has the effect of extending the average survival time by 27 days or more when administered alone at 3 mg / kg. When CsA and FK506 are administered alone, prolonged survival is observed at 30 mg / kg and 10 mg / kg for 30 days or longer, respectively.
[0039] 単独投与で生着延長作用が認められる投与量よりも低い用量で併用効果を試験し た結果を表 1に示した。 [0039] Table 1 shows the results of testing the combined effect at a dose lower than the dose at which the engraftment prolonging effect was observed when administered alone.
KNF-299は 3mg/kgの単独投与において明らかな移植片の生着延長作用が認めら れた。また、 CsA  KNF-299 was clearly shown to prolong graft survival when administered alone at 3 mg / kg. Also, CsA
30mg/kgの単独使用でも生着延長作用が認められた。 CsA 10mg/kg、 KNF-299 0.0 3mg/kgの投与ではコントロールに比し、 1〜4日の生着延長しか認められない投与量 であるが、両者を併用した場合は 30日以上の生着延長が全例で観察され、優れた拒 絶抑制効果が誘導できた。また、 FK506との場合も同様であり、低用量の単独投与で はほとんど効果が認められなかった力 FK506 3mg/kgと KNF-299 0.1mg/kgの併 用群では平均生着日数も 26日以上となり、明らかな併用効果が認められた。 Even when 30 mg / kg was used alone, the survival effect was observed. CsA 10 mg / kg, KNF-299 0.0 3 mg / kg is a dose that allows only 1 to 4 days longer than the control, but when both are used in combination, 30 days or longer An extension was observed in all cases, and an excellent rejection-inhibiting effect could be induced. This is also the case with FK506, with a single dose administered at a low dose. In the combination group of FK506 3 mg / kg and KNF-299 0.1 mg / kg, the mean survival time was 26 days or more, and a clear combination effect was observed.
[表 1] 表 1 ラット系統間の同種皮膚移植片の生着延長効果  [Table 1] Table 1 Effect of prolongation of allografts between rat strains
化合物（mg/kg,経口投与） 皮膚移植片の生看日数（曰）  Compound (mg / kg, oral administration) Number of days of skin graft life (曰)
N 個体別生着日数 ST Median 実験 1  N Number of survival days by individual ST Median Experiment 1
コントロール 5 8, 9, 9, 9， 10 9.0 9.0 Control 5 8, 9, 9, 9, 10 9.0 9.0
KNF-299 (3) 5 17, >30, >30，〉30, >30 〉27.4 >30KNF-299 (3) 5 17,> 30,> 30,〉 30,> 30〉 27.4> 30
CsA (30) 4 >30, >30, >30' >30 〉30 〉30 実験 2 CsA (30) 4> 30,> 30,> 30 '> 30〉 30〉 30 Experiment 2
コントローメレ 5 7, 8, 8, 8， 9, 9 8.0 8.0 Contromele 5 7, 8, 8, 8, 9, 9 8.0 8.0
CsA (10) 5 9， 1 1 , 12， 13, 14 1 1.8 12.0CsA (10) 5 9, 1 1, 12, 13, 13, 14 1 1.8 12.0
KNF-299 (0.03) 5 8, 9, 9, 9, 10 9.0 9.0KNF-299 (0.03) 5 8, 9, 9, 9, 10 9.0 9.0
CsA(10) + KNF-299(0.03) 4 >30, >30, >30, >30 >30 〉30 実験 2 CsA (10) + KNF-299 (0.03) 4> 30,> 30,> 30,> 30> 30〉 30 Experiment 2
コントロール 5 7, 7, 8, 9, 9 8.0 8.0 Control 5 7, 7, 8, 9, 9 8.0 8.0
FK506 (3) 5 9, 9, 9， 9, 10 9.2 9.0FK506 (3) 5 9, 9, 9, 9, 10 9.2 9.0
KNF-299 (0.1 ) 5 8, 8, 9， 9, 10 8.8 9.0KNF-299 (0.1) 5 8, 8, 9, 9, 10 8.8 9.0
FK506(3) + KNF-299(0.1 ) 5 13, >30, >30' >30, >30 >26.6 >30 FK506 (3) + KNF-299 (0.1) 5 13,> 30,> 30 '> 30,> 30> 26.6> 30
[0041] 以上のように KNF-299の併用により、 CsAや FK506といったカルシ-ユーリン阻害薬 の効果を増強し得ることが明らかとなった。カルシュ-ユーリン阻害薬の使用量を減 量できることで、臨床における腎毒性や肝毒性発現による使用制限を回避できる可 能性を増大し、効果的な治療法を提供するものである。 [0041] As described above, it has been clarified that the combined use of KNF-299 can enhance the effects of calciurin inhibitors such as CsA and FK506. The ability to reduce the amount of Kalsh-Eurin inhibitor used increases the possibility of avoiding restrictions on clinical use due to the development of nephrotoxicity and hepatotoxicity, and provides an effective treatment.
実施例 2  Example 2
[0042] ラットアジュバント閗節炎モデルにおけるメトトレキセート (MTX) の併用効菜  [0042] Combined effect of methotrexate (MTX) in rat adjuvant ganglionitis model
LEW/Crj系雌性ラット（日本チヤ一ルス ·リバ一） 6または 7週齢の右後肢足躕部皮 内に、流動パラフィンに懸濁した M.butyricum死菌 (12mg/mL)を 0.05ml(0.6mg/匹)ず つ注射し、関節炎を惹起した (DayO)。被験化合物は純水に溶解または懸濁し、ラット の体重 100g当り 0.5mlずつ経口投与した。 Adjuvant  LEW / Crj female rats (Japan Challus Riva) 0.05 ml of M. butyricum dead bacteria (12 mg / mL) suspended in liquid paraffin in the right hind paw skin of 6 or 7 weeks old 0.6 mg / animal) was injected each time to induce arthritis (DayO). The test compound was dissolved or suspended in pure water and orally administered at 0.5 ml per 100 g of rat body weight. Adjuvant
controlには純水のみを投与した。また、併用投与群は、 KNF-299の水溶液と MTX (Si gma)の水溶液を、投与前に混合して投与した。投与は DayOより実験終了まで 1日 1回 、連日行った。  Only pure water was administered to control. In the combined administration group, an aqueous solution of KNF-299 and an aqueous solution of MTX (Sigma) were mixed before administration. The administration was carried out once a day every day from DayO until the end of the experiment.
[0043] 関節炎の評価は、ボリュームメーター (MK-550、室町機械)を用いて、左右後肢の容 積を Day0,3,8,14,17, [0043] Arthritis was evaluated using a volume meter (MK-550, Muromachi Kikai). The product is Day0,3,8,14,17,
21に測定し、 DayOの後肢容積に対する増加量を求めた。  Measured at 21 and determined the increase in DayO hindlimb volume.
[0044] KNF-299のアジュバント関節炎の発症予防効果は濃度依存性があり、 0.1mg/kgで ほぼ最大に達する (図 1)。また、 MTXの発症予防効果は、 0.03mg/kgでは認められず[0044] The effect of KNF-299 in preventing the onset of adjuvant arthritis is concentration-dependent and reaches a maximum at 0.1 mg / kg (Fig. 1). In addition, the onset prevention effect of MTX was not observed at 0.03 mg / kg.
、 0.1mg/kgで最大に達する (図 2)。 The maximum is reached at 0.1 mg / kg (Figure 2).
[0045] そこで、それぞれの単独投与ではほとんど効果の期待できない投与量の組み合わ せにおいて、その併用効果を検討した。 KNF-299の投与量を 0.01mg/kgとし、 MTXの 投与量は 0.025mg/kg及び 0.05mg/kgとした。結果を図 3に示した。 [0045] Therefore, the effect of the combined use was examined in a combination of doses that could hardly be expected to be effective with each single administration. The dose of KNF-299 was 0.01 mg / kg, and the dose of MTX was 0.025 mg / kg and 0.05 mg / kg. The results are shown in FIG.
[0046] MTXは、 0.025mg/kg及び 0.05mg/kg単独投与で 20%及び 35%の抑制率を示したが[0046] MTX showed inhibition rates of 20% and 35% when 0.025 mg / kg and 0.05 mg / kg alone were administered.
、有意な作用ではなかった (Day21)。 KNF-299は、 0.01mg/kg単独投与で 36%(Day21It was not significant (Day 21). KNF-299 is 36% (Day 21
)抑制率を示した。 KNF-299 ) Inhibition rate was shown. KNF-299
0.01mg/kgと MTXを併用すると併用効果が認められ、 MTX 0.05mg/kgとの併用 では 84%の抑制率を示した。  When combined with 0.01 mg / kg and MTX, a combined effect was observed, and when combined with MTX 0.05 mg / kg, the suppression rate was 84%.
[0047] MTXは葉酸代謝拮抗剤であり、副作用として骨髄抑制、間質性肺炎等が起こること が知られて 、る。 KNF-299は臨床で最も有効性が高く第一選択薬である MTXと併用 することで、 AAモデルに対して優れた併用効果を示すことが明らかとなった。従って 、MTXの効果が現れにくい難治性のリウマチ患者に対して KNF-299を併用すること で、有効性を示すと思われる。また、 MTXは副作用が強い薬剤であり、リウマチ治療 では少量パルス療法を行っている。この場合でも副作用が発現することがあり、葉酸 を併用して副作用の軽減が図られて 、る。 MTXに KNF-299を併用することで MTXや KNF-299の投与量を減量でき、副作用を回避でき、安全性の高い治療法を提供し得 る。 [0047] MTX is a folic acid anti-metabolite and is known to cause bone marrow suppression, interstitial pneumonia, etc. as side effects. It became clear that KNF-299 has an excellent combination effect on the AA model when used in combination with MTX, which is the most effective first-line drug in clinical practice. Therefore, it seems to be effective by using KNF-299 in combination with refractory rheumatism patients who are less effective for MTX. MTX is a drug with strong side effects, and a small amount of pulse therapy is used for the treatment of rheumatism. Even in this case, side effects may occur, and side effects can be reduced by using folic acid together. By using KNF-299 in combination with MTX, the dose of MTX or KNF-299 can be reduced, side effects can be avoided, and a highly safe treatment can be provided.
実施例 3  Example 3
[0048] 耍 織;商合遣伝早^!合体 (MHC)不；商合ラット 統間に: けるミコフ ノール酸 ( MPA の并用による心移植 の ¾ ^ カ  [0048] Satoshi; Merchant Exchanges ^! Union (MHC); Merchant Rats: Mikoffanolic acid (synthetic heart transplantation using MPA)
MHCが不一致なラット同種異系間の心移植において KNF-299の作用を検討した。ド ナ一として DA(RlT)ラット、レシピエントとして LEW (RT11)ラットの組み合わせで、ド ナ一の心臓をレシピエントの頸部血管にカフで接合する異所性心移植を文献 (Micro surgery; We investigated the effect of KNF-299 in allogeneic heart transplantation in rats with mismatched MHC. Ectopic heart transplantation using a combination of DA (RlT) rats as donors and LEW (RT1 1 ) rats as recipients, cuffing the donor's heart to the recipient's cervical blood vessels (Micro surgery;
21,16-21, 2001)等を参考にして施した。  21, 16-21, 2001).
薬物の投与は、心移植当日力ゝら、 1日 1回、毎日、経口投与で行った。 MPAは和光 純薬力 購入したものを 0.5%  The drug was administered by oral administration once a day, every day, on the day of heart transplantation. MPA is 0.5% of Wako Junyaku purchased
カルボキシメチルセルロース、 0.4% Tween80、および 0.9%ベンジルアルコール含有 生理食塩水で 20mg/mLになるように調製し、 O.lmL/lOOgB.W.で投与した  Carboxymethylcellulose, 0.4% Tween80, and 0.9% benzyl alcohol-containing physiological saline was prepared to 20 mg / mL and administered at O.lmL / lOOgB.W.
。 KNF-299は蒸留水に 0.06mg/mLに溶解し、 0.5mL/100g  . KNF-299 dissolves in distilled water at 0.06mg / mL, 0.5mL / 100g
B.W.で投与した。コントロール群には MPA投与液に使用した溶媒を投与した。  B.W. The control group received the solvent used in the MPA administration solution.
移植心臓の心拍動を視診または触診にて確認し、心拍動の停止をもって拒絶と判 断した。移植力も拒絶が確認されるまでの日数を生着期間とした。各群の生着期間 の平均値を平均生着日数 (MST)として算出した。拒絶反応を強く引き起こす系統間 の組み合わせにお  The heartbeat of the transplanted heart was confirmed by visual inspection or palpation, and it was judged as rejection when the heartbeat stopped. The number of days until the rejection of transplantation was confirmed was taken as the engraftment period. The average value of the survival period of each group was calculated as the average number of survival days (MST). For combinations between strains that strongly cause rejection
いて、移植心臓の拒絶抑制作用を検討した結果を表 2に示した。  Table 2 shows the results of studying the rejection suppression effect of the transplanted heart.
[0049] [表 2] 表 2 ラット系統間の 心蔵の 延^果 [0049] [table 2] table 2
化合物 （rn^kg,経口投与） 移植心臓の生着日数 （日）  Compound (rn ^ kg, oral) Days of transplanted heart survival (days)
N 個体別生着日数 MST コントロール 5 5, 6, 6， 6, 6 5. 8 N Number of survival days by individual MST control 5 5, 6, 6, 6, 6 5. 8
MPA (20) 7 18, 26, 34, 50, 53, >100， 〉100 >54.4MPA (20) 7 18, 26, 34, 50, 53,> 100,〉 100> 54.4
KNF-299 (0. 3) 5 6, 7, 7, 7, 8 7.0KNF-299 (0. 3) 5 6, 7, 7, 7, 8 7.0
MPA (20) + KNF-299 (0. 3) 6 〉100, 00， 〉100, >100, 〉100， 〉100 >100 MPA (20) + KNF-299 (0.3) 6〉 100, 00,〉 100,> 100,〉 100,〉 100> 100
[0050] その結果、 KNF-299の 0.3mg/kg単独投与では 7.0日の平均生着日数であり、コント ロール群に比して 1.2日と僅かな延長作用し力認められなかった。また、 MPAは 20mg /kg単独投与では高用量にもかかわらず、生着日数に個体差が大きく拒絶抑制作用 は不十分であった。両者を併用した場合、全例で 100日以上の生着日数の延長が認 められ、明らかに併用作用がもたらされることが示された。 [0050] As a result, when 0.3 mg / kg of KNF-299 alone was administered, the average number of days of survival was 7.0 days, and it was slightly increased and 1.2 days compared with the control group, and no force was observed. In addition, when MPA alone was administered at a dose of 20 mg / kg, despite the high dose, there were large individual differences in the number of days of survival, and the inhibitory effect on rejection was insufficient. When both were used in combination, an extension of the survival period of 100 days or more was observed in all cases, and it was clearly shown that the combined action was brought about.
産業上の利用可能性  Industrial applicability
[0051] 臓器移植の際には、末梢を循環するリンパ球を減少させる作用を有し 2—アミノー 1 , 3—プロパンジオール構造を有するジァリールスルフイド又はジァリールエーテル化 合物は単剤でも優れた免疫抑制効果を示す力 S、カルシ-ユーリン阻害剤である CsA や FK506、ヌクレオシド合成阻害であるミコフ ノール酸 (MPA)などの免疫抑制剤や 抗炎症剤との併用により、その効果を増強する。それ故、臨床における CsA、 FK506 、ミコフエノール酸モフエチルの投与量を減量できることで、カルシ-ユーリン剤の腎 毒性や肝毒性あるいはヌクレオシド合成阻害剤の好中球減少などによる使用制限を 回避でき、安全性の高い効果的な治療法を提供できる。また、リウマチ治療の際にも 、本出願の方法によればメトトレキサートの投与量を減量でき、副作用の回避と安全 性の高い治療法を提供できる。つまり、組み合わされる薬剤が少量でも十分な抗炎 症効果が発現することで、安全に長期間使用することが可能になりリウマチの病態の 進行や再発を効果的にかつ持続的に抑制することが期待できる。 [0051] In organ transplantation, diarylsulfide or diaryletherification which has the effect of reducing lymphocytes circulating in the periphery and has a 2-amino-1,3-propanediol structure Combined with a combination of immunosuppressive and anti-inflammatory agents such as C, which is an excellent immunosuppressive effect even with a single agent, CsA and FK506, which are calcineurin inhibitors, and myco-funolic acid (MPA), which is a nucleoside synthesis inhibitor To enhance the effect. Therefore, the clinical doses of CsA, FK506, and mofethyl mycophenolate can be reduced, so that the use of calciurin drugs due to nephrotoxicity or hepatotoxicity or nucleoside synthesis neutropenia can be avoided, which is safe. A highly effective treatment can be provided. Also, in the treatment of rheumatism, according to the method of the present application, the dose of methotrexate can be reduced, and side effects can be avoided and a highly safe treatment can be provided. In other words, a sufficient anti-inflammatory effect can be achieved even with a small amount of the combined drug, and it can be used safely for a long period of time, effectively and continuously suppressing the progression and recurrence of rheumatic conditions. I can expect.
従って、本発明の末梢を循環するリンパ球を減少させる作用を有し 2 アミノー 1, 3 プロパンジオール構造を有するジァリールスルフイド又はジァリールエーテル化合 物と免疫抑制剤及び Z又は抗炎症剤とを組み合せてなる医薬は、免疫抑制作用や 抗炎症作用を効果的に発現させ、且つ副作用発現を減少させる手段として有用であ る。このような医薬は自己免疫疾患および病原微生物 ·外来抗原 ·外因性物質による 炎症の予防または治療や炎症性、増殖性および高増殖性の皮膚病および皮膚に現 れる免疫原媒介性疾患の予防および治療に有用である。  Therefore, the present invention has the effect of reducing lymphocytes circulating in the periphery of a 2-amino-1,3-propanediol structure, a diarylsulfide or a diarylether compound, an immunosuppressive agent, and a Z or antiinflammatory agent. A pharmaceutical comprising a combination of and is useful as a means for effectively expressing an immunosuppressive action and an anti-inflammatory action and reducing the occurrence of side effects. Such drugs are used to prevent or treat inflammation caused by autoimmune diseases and pathogenic microorganisms, foreign antigens, exogenous substances, and prevent inflammatory, proliferative and hyperproliferative skin diseases and immunogen-mediated diseases that appear in the skin. Useful for treatment.

Claims

請求の範囲 The scope of the claims
[1] 末梢を循環するリンパ球を減少させる作用を有し 2 アミノー 1, 3 プロパンジォー ル構造を有するジァリールスルフイド又はジァリールエーテルィ匕合物と、免疫抑制剤 及び Z又は抗炎症剤とを組み合わせてなる医薬。  [1] Diarylsulfide or diarylether compound having an action to reduce lymphocytes circulating in the periphery and having 2 amino-1,3 propanediol structure, immunosuppressant and Z or anti-inflammatory A medicine that is combined with an agent.
[2] 末梢を循環するリンパ球を減少させる作用を有し 2 アミノー 1, 3 プロパンジォー ル構造を有するジァリールスルフイド又はジァリールエーテルィ匕合物が一般式（1)[2] A diarylsulfide or diarylether compound having an action of reducing lymphocytes circulating in the periphery and having a 2-amino-1,3-propanediol structure is represented by the general formula (1)
[化 1]
Figure imgf000017_0001
[Chemical 1]
Figure imgf000017_0001
[式中、 Rはハロゲン原子、トリハロメチル基、ヒドロキシ基、炭素数 1〜7の低級アル キル基、置換基を有しても良いフエ二ル基、ァラルキル基、炭素数 1〜4の低級アル コキシ基、トリフルォロメチルォキシ基、フエノキシ基、シクロへキシルメチルォキシ基 、置換基を有しても良いァラルキルォキシ基、ピリジルメチルォキシ基、シンナミルォ キシ基、ナフチルメチルォキシ基、フエノキシメチル基、ヒドロキシメチル基、ヒドロキシ ェチル基、炭素数 1〜4の低級アルキルチオ基、炭素数 1〜4の低級アルキルスルフ ィニル基、炭素数 1〜4の低級アルキルスルホ-ル基、ベンジルチオ基、ァセチル基 、ニトロ基又はシァノ基を示し、 Rは水素原子、ハロゲン原子、トリノ、ロメチル基、炭素 [In the formula, R is a halogen atom, a trihalomethyl group, a hydroxy group, a lower alkyl group having 1 to 7 carbon atoms, a phenyl group that may have a substituent, an aralkyl group, or a lower group having 1 to 4 carbon atoms. Alkoxy group, trifluoromethyloxy group, phenoxy group, cyclohexylmethyloxy group, aralkyloxy group, pyridylmethyloxy group, cinnamyloxy group, naphthylmethyloxy group, which may have a substituent, Phenoxymethyl group, hydroxymethyl group, hydroxyethyl group, lower alkylthio group having 1 to 4 carbon atoms, lower alkylsulfinyl group having 1 to 4 carbon atoms, lower alkylsulfol group having 1 to 4 carbon atoms, benzylthio group, and acetyl group , Nitro group or cyano group, R is hydrogen atom, halogen atom, torino, romethyl group, carbon
2  2
数 1〜4の低級アルコキシ基、炭素数 1〜7の低級アルキル基、フ ネチル基又はべ ンジルォキシ基を示し、 Rは水素原子、ハロゲン原子、トリフルォロメチル基、炭素数  Represents a lower alkoxy group having 1 to 4 carbon atoms, a lower alkyl group having 1 to 7 carbon atoms, a phenethyl group or a benzyloxy group, and R represents a hydrogen atom, a halogen atom, a trifluoromethyl group, or a carbon number.
3  Three
1〜4の低級アルコキシ基、ヒドロキシ基、ベンジルォキシ基、炭素数 1〜7の低級ァ ルキル基、フエ-ル基、炭素数 1〜4の低級アルコキシメチル基又は炭素数 1〜4の 低級アルキルチオ基を示し、 Xは 0、 S、 SO又は SOを示し、 nは 1〜4の整数を示す  1 to 4 lower alkoxy group, hydroxy group, benzyloxy group, 1 to 7 carbon lower alkyl group, phenol group, 1 to 4 carbon lower alkoxymethyl group or 1 to 4 carbon lower alkylthio group X represents 0, S, SO or SO, n represents an integer of 1 to 4
2  2
]で表される化合物又は薬学的に許容される塩ならびに水和物である請求項 1記載 の医薬。  The medicament according to claim 1, which is a compound represented by the formula:
前記一般式（1)で表される化合物が 2 ァミノ一 2— [4一（3 ベンジルォキシフエ -ルチオ） 2 クロ口フエ-ル]ェチルー 1, 3 プロパンジオールである請求項 2記 載の医薬。 3. The compound according to claim 2, wherein the compound represented by the general formula (1) is 2-amino-1,2- [4 (3-benzyloxyphenyl) -2-chlorophenyl] ethyl-1,3 propanediol. Medicine.
[4] 前記一般式（1)で表される化合物が 2 アミノー 2— [4一（3 べンジルォキシフエ 二ルチオ） 2 クロ口フエ-ル]ェチルー 1, 3 プロパンジオール塩酸塩である請求 項 2記載の医薬。 [4] The compound represented by the general formula (1) is 2-amino-2- [4 (3-benzyloxydithio) 2 chlorophenol] ethyl-1,3 propanediol hydrochloride. Medicines.
[5] 免疫抑制剤がカルシニューリン阻害薬である請求項 1記載の医薬。  5. The medicament according to claim 1, wherein the immunosuppressive agent is a calcineurin inhibitor.
[6] カルシュ-ユーリン阻害剤がシクロスポリン A又はタクロリムスである請求項 5記載の 医薬。 6. The medicament according to claim 5, wherein the carche-eurin inhibitor is cyclosporin A or tacrolimus.
[7] 免疫抑制剤がメトトキサレート又はミコフエノール酸若しくはミコフエノール酸モフエチ ルである請求項 1記載の医薬。  7. The medicament according to claim 1, wherein the immunosuppressive agent is methotoxalate, mycophenolic acid or mycophenolic acid methanol.
[8] 末梢を循環するリンパ球を減少させる作用を有し 2 ァミノ一 1, 3 プロパンジォー ル構造を有するジァリールスルフイド又はジァリールエーテルィ匕合物と、免疫抑制剤 及び Z又は抗炎症剤とを組み合せてなる医薬により、相互の薬効を増強し、また、使 用量を減少させることで副作用発現の防御に関する方法。 [8] Diarylsulfide or diarylether compound having an action to reduce lymphocytes circulating in the periphery and having a 2-amino-1,3-propanediol structure, an immunosuppressant and Z or anti A method related to the prevention of side effects by enhancing the mutual efficacy and reducing the dose by using a medicine combined with an inflammatory agent.
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